Processes for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof

ABSTRACT

The present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof of the formulas 
                         
which are useful as antihistamines, antiallergic agents and bronchodilators.

This is a continuation of application Ser. No. 09/803,389, filed Mar. 9,2001 now abandoned, which is a continuation of application Ser. No.09/213,554, filed Dec. 17, 1998, now abandoned, which is a continuationof application Ser. No. 08/815,640, filed Mar. 13, 1997, now abandoned,which is a continuation of application Ser. No. 08/417,161, filed Apr.11, 1995, now abandoned, which is a continuation-in-part of Ser. No.08/245,731, filed May 18, 1994, now abandoned.

the present invention is related to novel processes for preparinganhydrous and hydrated forms of piperidine derivatives, polymorphs andpseudomorphs thereof which are useful as antihistamines, antiallergicagents and bronchodialators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S.Pat. No. 4,245,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25,1981].

SUMMARY OF THE INVENTION

The present invention provides a process for preparing anhydrous,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formulas.

wherein

-   -   R₁ represents hydrogen or hydroxy;    -   R₂ represents hydrogen; or    -   R₁ and R₂ taken together form a second bond between the carbon        atoms bearing R₁ and R₂;    -   n is an integer of from 1 to 5;    -   R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety has        from 1 to 6 carbon atoms and is straight or branched;    -   each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof,

-   comprising subjecting the corresponding hydrated, pharmaceutically    acceptable acid addition salt to an azeotropic distillation.

In addition, the present invention also provides a process for preparinganhydrous, pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula

wherein

-   -   R₁ represents hydrogen or hydroxy;    -   R₂ represents hydrogen; or    -   R₁ and R₂ taken together form a second bond between the carbon        atoms bearing R₁ and R₂;    -   n is an integer of from 1 to 5;    -   R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety has        from 1 to 6 carbon atoms and is straight or branched;    -   each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof,

-   comprising subjecting the corresponding hydrated, pharmaceutically    acceptable acid addition salt to a water-minimizing    recrystallization.

In addition, the present invention provides a process for preparing thehydrated, pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula.

wherein

-   -   R₁ represents hydrogen or hydroxy;    -   R₂ represents hydrogen; or    -   R₁ and R₂ taken together form a second bond between the carbon        atoms bearing R₁ and R₂;    -   n is an integer of from 1 to 5;    -   R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety has        from 1 to 6 carbon atoms and is straight or branched;    -   each of A is hydrogen or hydroxy; and

pharmaceutically acceptable salts and individual optical isomersthereof,

-   comprising subjecting the corresponding anhydrous, pharmaceutically    acceptable acid addition salts to an aqueous recrystallization.

In addition, the present invention provides processes for preparingpolymorphs of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride designated herein as Form I and Form III andprocesses for preparing psuedomorphs of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride designated herein as Form II and Form IV.

The Form I polymorph may be identified by the following characteristics:a visual melting point (capillary tube) in the range of about 196–201°C.; a melt endotherm with extrapolated onset in the range of about195–199° C. as determined by differential scanning calorimetry; and anX-ray powder diffraction pattern essentially as shown in Table 1 whereinthe XRPD patterns were measured using a powder diffractometer equippedwith a Co X-ray tube source. The sample was illuminated with Co Kα₁radiation and XRPD data were collected from 5 to 55° 2⊖. (intensitiesmay vary radically due to preferred orientation).

TABLE 1 D-Space, Angstroms Intensity, I/I_(o), % 11.8 30 7.3 30 6.3 655.9 35 5.0 45 4.8 100 4.4 45 3.9 60 3.8 75 3.7 30

The Form III polymorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 166–171° C.; a broad endotherm below about 90° C., a meltendotherm with an extrapolated onset of about 166° C. as determined bydifferential scanning calorimetry; and an X-ray powder diffractionpattern essentially as shown in Table 2 wherein the XRPD patterns weremeasured using a powder diffractometer equipped with a Co X-ray tubesource. The sample was illuminated with Co Kα₁ radiation and XRPD datawere collected from 5 to 55° 2⊖. (intensities may vary radically due topreferred orientation).

TABLE 2 D-Space, Angstroms Intensity, I/I_(o), % 9.0 95 4.9 100 4.8 354.6 25 4.5 25 3.7 25

The Form II pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 100–105° C.; a large broad endotherm below about 100° C. and asmall endothermic peak (about 2 joules/gram) with extrapolated onsets inthe range of about 124–126° C. as determined by differential scanningcalorimetry; and an X-ray powder diffraction pattern essentially asshown in Table 3 wherein the XRPD patterns were measured using a powderdiffractometer equipped with a Co X-ray tube source. The sample wasilluminated with Co Kα₁ radiation and XRPD data were collected from 5 to55° 2⊖. (intensities may vary radically due to preferred orientation).

TABLE 3 D-Space, Angstroms Intensity, I/I_(o), % 7.8 45 6.4 44 5.2 854.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50

The Form IV pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 113–118° C.; two broad overlapping endotherms below about 100° C.and an additional endotherm with an extrapolated onset at approximately146° C. as determined by differential scanning calorimetry and an X-raypowder diffraction pattern essentially as shown in Table 4 wherein theXRPD patterns were measured using a powder diffractometer equipped witha Co X-ray tube source. The sample was illuminated with Co Kα₁ radiationand XRPD data were collected from 5 to 55° 2⊖. (intensities may varyradically due to preferred orientation).

TABLE 4 D-Space, Angstroms Intensity, I/I_(o), % 10.4 60 7.0 45 6.4 505.3 100 5.2 55 4.3 75 4.1 50 4.0 45 3.8 60 3.5 55

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutically acceptable acid addition salts of the compounds offormula (I) and (II), both anhydrous and hydrated, are those of anysuitable inorganic or organic acid. Suitable inorganic acids are, forexample, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.Suitable organic acids include carboxylic acids, such as, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic,tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, anddihydroxymnaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids,such as, methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonicacid.

As used herein, the term “hydrate” refers to a combination of water witha compound of formula (I) or (II) wherein the water retains itsmolecular state as water and is either absorbed, adsorbed or containedwithin a crystal lattice of the substrate molecule of formula (I) or(II).

As used herein, the term “adsorped” refers to the physical state whereinthe water molecule in the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) isdistributed over the surface of the solid hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II).

As used herein, the term “absorbed” refers to the physical state whereinthe water molecule in the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) isdistributed throughout the body of the solid hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II).

Hydrated, pharmaceutically acceptable acid addition salts of thecompounds of formula (I) and (II) are those hydrates ranging fromessentially 0.10 to 5 molecules of water per molecule of substrate saltof formula (I) or (II).

As used herein, the term “azeotropic mixture” refers to a liquid mixtureof two or more substances which behaves like a single substance in thatthe vapor produced by partial evaporation of liquid has the samecomposition as the liquid. The constant boiling mixture exhibits eithera maximum or minimum boiling point as compared with that of othermixtures of the same substance.

As used herein, the term “azeotropic distillation” refers to a type ofdistillation in which a substance is added to the mixture to beseparated in order to form an azeotropic mixture with one or more of theconstituents of the original mixture. The azeotrope or azeotropes thusformed will have boiling points different from the boiling points of theoriginal mixture. As used herein, the term “azeotropic distillation”also refers to co-distillation.

As used herein, the term “water-minimizing recrystallization” refers toa recrystallization wherein the ratio of anhydrous solvent to substratehydrate is such that the percentage of water present is minimized,thereby inducing precipitation of the anhydrous form of the substrate.

As used herein, the term “aqueous recrystallization” refers to thoseprocesses wherein either 1) a solid material is dissolved in a volume ofwater or a water/organic solvent mixture sufficient to cause dissolutionand the solid material recovered by evaporation or the solvent; 2) asolid material is treated with a minimal amount of water or awater/organic solvent mixture which is not sufficient to causedissolution, heated to obtain dissolution and cooled to inducecrystallization or 3) a solid material is dissolved in a volume of wateror a water/organic solvent mixture sufficient to cause dissolution andthen the solvent is partially evaporated to form a saturated solutionwhich induces crystallization.

As used herein, the term “crystal digestion” refers to that processwherein a solid material is treated with a minimal amount of water orwater/organic solvent mixture which is not sufficient to causedissolution and either heating or stirring at ambient temperature untilthe desired transformation has taken place.

As used herein, the term “antisolvent” refers to a poor solvent for thesubstance in question which when added to a solution of the substance,causes the substance to precipitate.

As used herein, the term “suitable temperature” refers to thattemperature which is sufficient to cause dissolution and to permit theprecipitation of the desired substance either upon addition of anantisolvent or upon removal of the co-solvent by azeotropicdistillation.

The anhydrous, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) and (II) may be prepared fromthe corresponding hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II) bysubjecting the corresponding hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) toan azeotropic distillation.

For example, the appropriate hydrated, pharmaceutically acceptable acidaddition salt of piperidine derivatives of the formula (I) and (II) isfirst dissolved in a volume of a suitable solvent or solvent mixturewhich is sufficient to cause dissolution. Examples of such solvents arewater, C₁–C₅ alkanols such as methanol, ethanol and the like; ketonesolvents such as acetone, methyl ethyl ketone and the like; aliphaticester solvents such as ethyl acetate, methyl acetate, methyl formate,ethyl formate, isopropyl acetate and the like and aqueous mixtures ofthese solvents, such as acetone/water, methyl ethyl ketone/water,water/acetone and water/acetone/ethyl acetate. An additional volume ofthe same solvent used to effect dissolution or second suitable anhydrousantisolvent is then added to this solution, which is then heated to aboiling point which is suitable to azeotropically remove water and otherlow boiling components. Suitable anhydrous antisolvents for use in theazeotropic distillation are, for example, ketone solvents such asacetone, methyl ethyl ketone and the like; aliphatic ester solvents suchas ethyl acetate, methyl acetate, methyl formate, ethyl formate,isopropyl acetate and the like; C₅–C₈ aliphatic solvents such aspentane, hexane and the like; aliphatic nitriles, such as acetonitrileand mixtures of these solvents such as acetone/ethyl acetate and thelike. The azeotropic mixture of water and solvent is removed bydistillation until the temperature changes, indicating that theazeotropic mixture is completely removed. The reaction mixture is cooledand the corresponding anhydrous, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) isrecovered from the reaction zone by, for example filtration.

In addition, the anhydrous, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II) may beprepared from the corresponding hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) by subjecting the corresponding hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II) to a water-minimizing recrystallization.

For example, the appropriate hydrated, pharmaceutically acceptable acidaddition salt of piperidine derivatives of the formula (I) and (II) isdissolved in a volume of a suitable anhydrous solvent or solvent mixturewhich is sufficient to cause dissolution and heated to reflux. Examplesof such solvents are water, C₁–C₅ alkanols such as methanol, ethanol andthe like; ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like andaqueous mixtures of these solvents, such as acetone/water, methyl ethylketone/water, water/acetone and water/acetone/ethyl acetate. Anadditional volume of the same solvent used to effect dissolution orsecond suitable anhydrous antisolvent is then added in a quantitysufficient to initiate precipitation of the anhydrous, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II). Suitable anhydrous antisolvents are, for example, ketonesolvents such as acetone, methyl ethyl ketone and the like; aliphaticester solvents such as ethyl acetate, methyl acetate, methyl formate,ethyl formate, isopropyl acetate and the like; mixtures of ketonesolvents and aliphatic ester solvents such as acetone/ethyl acetate andthe like; C₅–C₈ aliphatic solvents such as pentane, hexane and the like;aliphatic nitriles, such as acetonitrile and mixtures of these solventssuch as acetone/ethyl acetate and the like as well as mixtures of waterand ketone solvents such as acetone/water and the like; and mixtures ofwater, ketone solvents and aliphatic ester solvents such asacetone/water/ethyl acetate. The reaction mixture is cooled and thecorresponding anhydrous, pharmaceutically acceptable acid addition saltof piperidine derivatives of the formula (I) and (II) is recovered fromthe reaction zone by, for example filtration.

Polymorphic forms of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms I and III) may be prepared by a variety ofmethods as detailed below.

Form III to Form I

For example, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III), by subjecting the anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) to a crystal digestion as described above.

Form II to Form III

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above.

Form II to Form I

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above or by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an azeotropic distillation.

Form IV to Form I

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) to water-minimizing recrystallization or toan azeotropic distillation as described above.

The hydrated, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) may be prepared from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl bysubjecting the corresponding compound of the formula (II) wherein R₃ is—COOalkyl to a reduction using an appropriate reducing agent, such assodium borohyride, potassium borohydride, sodium cyanoborohydride, ortetramethylammonium borohydride in a suitable solvent, such as,methanol, ethanol, isopropyl alcohol or n-butanol, aqeuous mixturesthereof or basic solutions thereof, at temperatures ranging from about0° C. to the reflux temperature of the solvent, and the reaction timevaries from about ½ hour to 8 hours. After quenching and acidifying withan suitable acid, such as hydrochloric acid, the hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) are recovered from the reaction zone bycrystallization and filtration.

In addition, the hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II) may beprepared from the corresponding anhydrous, pharmaceutically acceptableacid addition salts of the formula (I) and (II) by subjecting thecorresponding anhydrous, pharmaceutically acceptable acid addition saltsof formula (I) and (II) to an aqueous recrystallization.

For example, the appropriate anhydrous, pharmaceutically acceptable acidaddition salt of piperidine derivatives of the formula (I) and (II) istreated with a minimal volume of water or suitable water/organic solventmixture which is insufficient to cause dissolution and heated to reflux.The reaction mixture is cooled and the corresponding hydrated,pharmaceutically acceptable acid addition salt of piperidine derivativesof the formula (I) and (II) is recovered from the reaction zone by, forexample filtration. Alternatively, the appropriate anhydrous,pharmaceutically acceptable acid addition salt of piperidine derivativesof the formula (I) and (II) is treated with a volume of water or asuitable water/organic solvent mixture which is sufficient to causedissolution and the water or water/organic solvent is partially orcompletely evaporated to a volume which induces crystallization of thehydrated, pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II). Suitable solvents for use inthe above recrystallization are water, acetone/water, ethanol/water,methyl ethyl ketone/aqueous methanol, methyl ethyl ketone/water and thelike.

The pseudomorphic forms of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms II and IV) may be prepared by a variety ofmethods as detailed below.

Ethyl Ester/Ketone to Form II

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl, butrapdily adding water over a period of time ranging from 1 minute to 45minutes at a temperature range of about −20° C. to 50° C. to precipitatethe hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II).

Ethyl Ester/Ketone to Form IV

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl, butslowly adding water over a period of time ranging from about 30 minutesto 24 hours and at a temperature range of about 0° C. to 50° C.,optionally with seeding, to precipitate the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV).

Form I to Form II

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) by subjecting hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an aqueous recrystallization as definedabove.

Starting materials for use in the present invention are readilyavailable to one of ordinary skill in the art. For example, ethyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride is described in U.S. Pat. 4,254,129, Mar. 3, 1981.

The following examples present typical processes for preparing theanhydrous and hydrated, pharmaceutically acceptable acid addition saltsof piperidine derivatives of the formula (I) and (II), polymorphs andpseudomorphs therof. These examples are understood to be illustrativeonly and are not intended to limit the scope of the present invention inany way. As used herein, the following terms have the indicatedmeanings: “g” refers to grams; “mol” refers to mole; “mmol” refers tomillimoles; “mL” refers to milliliters; “bp” refers to boiling point;“mp” refers to melting point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

Differential Scanning Calorimetry analysis were performed using a TA2910 DSC with open aluminum pans. The samples were heated to 240° C. at5° C./minute with a 50 mL/minute nitrogen purge.

X-Ray Powder Diffraction analyses were performed as follows:

The samples were loaded into a quartz (zero scatter) sample holder forthe XRPD pattern measurement. The XRPD patterns were measured using apowder diffractometer equipped with a Co X-ray tube source, primary beammonochromator, and position sensitive detector (PSD). The incident beamwas collimated using a 1° divergence slit. The active area on the PSDsubtended approximately 5°2⊖. The source was operated at 35 kV and 30 mAand the sample was illuminated with Co Kα₁ radiation. XRPD data werecollected from 5 to 55° 2⊖ at a rate of 0.25°2⊖/minute and a step widthof 0.02°2⊖. The XRPD patterns were measured without the addition of aninternal calibrant.

Peak positions and intensities for the most prominent features weremeasured using a double-derivative peak picking method. X-ray peaks withI/I_(O) greater than 20% were reported. The cutoff was chosenarbitrarily. The intensities are rounded to the nearest 5%. Certainpeaks appear sensitive to preferred orientation that is caused bychanges in crystallite morphology. This results in large changes in theI/I_(O) value.

EXAMPLE 1 Preparation of Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

Method A

Mix ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (101.92 g, 0.1807 mol) and methanol (510 mL) and stir.Rapidly add 50% sodium hydroxide (72.27 g, 0.903 mol) and wash in withwater (61 mL). Heat to reflux for 2 hours, allow to cool to 35° C. andtreat with sodium borohydride (3.42 g, 0.0903 mol). Add water (100 mL)and maintain at 35° C. for 10 hours. Add 37% hydrochloric acid (53.0 g)to adjust pH to 11.5. Add acetone (26.5 mL) and water (102 mL). Hold at35° C. for 2 hours and adjust to pH 2.5 with 37% hydrochloric acid(44.69 g). Dilute with water (408 mL), cool to −15° C., stir for 1.5hours and collect the precipitate by vacuum filtration. Wash thefiltercake with deionized water (3×100 mL) and vacuum dry to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (97.10 g).

Method B

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (60.01 g, 0.106 mol) in a 1-L three necked round-bottomflask and fit the flask with a mechanical stirrer, a Claisen head, athermometer and a reflux condenser with a nitrogen bubbler on top. Addmethanol (300 mL) and turn the stirrer on. Dilute the slurry with water(6 mL) and heat to 52–54° C. over 15–20 minutes. Hold at 52° C. for 2hours and then add 50% sodium hydroxide (42.54 g, 0.532 mol). Heat at73° C. for approximately 1 hour, 45 minutes, cool to less than 35° C.using a water bath and then add sodium borohydride (2.02 g, 0.0534 mol).Stir overnight at 35° C., treat with acetone (15.5 mL) and stir for 2hours at 35° C. Acidify the mixture to a pH of 1.85 with 28%hydrochloric acid (75.72 g), dilute with water (282 mL), stir for about30 minutes and cool over about 2 hours to −15° C. Filter the solids offand wash with water (2×75 mL) and ethyl acetate (2×75 mL). Vacuum drythe solid and allow to stand for 2 days to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (57.97 g, 91.5%) as a fine powder.

Method C

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL). Addwater over about 30 minutes (192 mL), hold the temperature at 33° C. for10 minutes and add a few seed crystals. Cool the slurry to −12° C. overabout 45 minutes and isolate the solid by filtration (586.2 g). Washwith water (2×100 mL) and then with ethyl acetate (100 mL, prechilled toabout −10° C.). Vacuum dry overnight (1 mmHg, 50° C.) to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (58.86 g, 98%) as a white solid.

EXAMPLE 2 Preparation of Form IV4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

(Form IV)

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL).Hold the temperature at 33° C. for 10 minutes, add a few seed crystalsand add water over about 4 hours (192 mL) at 35° C. Cool the slurry to−12° C. over about 45 minutes and isolate the solid by filtration (586.2g). Wash with water (2×100 mL) and then with ethyl acetate (100 mL,prechilled to about −10° C.). Vacuum dry overnight (1 mmHg, 50° C.) togive4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV); mp 115–116° C. (dec).

XRPD: Table 5

TABLE 5 D-Space, Angstroms Intensity, I/I_(o), % 10.38 60 6.97 45 6.4150 5.55 30 5.32 100 5.23 55 5.11 35 4.98 25 4.64 30 4.32 35 4.28 75 4.1250 4.02 45 3.83 60 3.65 20 3.51 55 3.46 25 2.83 20

EXAMPLE 3 Conversion of Form II to Form I4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride

(Form I)

Treat 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (20.0 g,0.0355 mol) with deionized water (2 g) and add acetone (60 mL) in smallportions over several minutes with stirring. Filter through filter aidand wash the filter cake with acetone (30 mL). Wash the filtercake withacetone (22 mL), reflux filtrate and then slowly add ethyl acetate (32mL over 15 minutes) keeping the mixture at reflux. Reflux for 10minutes, then slowly add additional ethyl acetate (23 mL over 10minutes) and reflux for an additional 15 minutes. Add additional ethylacetate (60 mL over 5–10 minutes) and continue refluxing for 15 minutes.Cool to approximately 8° C. in an ice bath, filter the solid and washwith ethyl acetate (85 mL). Vacuum dry at 55° C. for 1.5 hours to givethe title compound (18.16 g, 95%).

EXAMPLE 4 Conversion of Form II to Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

Method A

Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (5.00 g, 0.0083 mol) withmethylethyl ketone (130 mL). Slowly add water (0.4 mL), filter throughfilter aid and wash the filter cake with methylethyl ketone (20 mL).Heat to reflux and distill off 75 mL of solvent, cool to −15° C. andcollect by vacuum filtration. Wash with inethylethyl ketone (2×10 mL)and vacuum dry at 60° C. to give the title compound (4.33 g, 97%); mp196–198° C.

Method B

Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (1.4 g) with acetone (60 mL) andheat to reflux. Reduce the volume to approximately 35 mL to remove allwater which boils off as an azeotrope (88/12:acetone/water). Cool thesolution and collect the title compound as a crystalline solid.

Method C

Mix4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (53.88 g, 0.100 mol) and add water(4.79 g) and methyl ethyl ketone (240 mL). Stir until the solid isslurried up and add additional methyl ethyl ketone (1 L) Stir for 0.5hours, filter through a pad of filter aid, wash the filtercake withmethyl ethyl ketone (100 mL) and transfer the filtrate and wash to a 2L, 3-necked flask fitted with a thermometer, mechanical stirrer anddistillation head. Distill off a total of 721 mL of methyl ethyl ketone,cool and stir over 1 hour to 40° C. Cool to −15° C. and hold for 10minutes. Collect the solid by vacuum filtration and wash the filtercakewith methyl ethyl ketone (2×65 mL) and vacuum dry at 55° C. overnight togive the title compound (52.76 g, 97.9%); mp 197.5–200° C.

Method D

Treat 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (40.0 g,0.0696 mol, assayed at 93.6% purity, having 0.89 g water present and35.1 g, 0.0575 mol, assayed at 88.0% purity, having 2.47 g waterpresent) with water (8.30 g; the amount calculated to bring the weightof water present to 17% of the anhydrous weight of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate, taking into accountthe water in the hydrated salt). Add methyl ethyl ketone (approximately500 mL) and stir until most of the solids dissolve. Add additionalmethyl ethyl ketone (700 mL) in portions over approximately 10 minutesand continue stirring for ½ hour. Filter through a thin pad of filteraid, wash the filtercake and flask with additional methyl ethyl ketone(100 mL) and transfer to a boiling flask fitted with a thermometer,mechanical stirrer, heating mantle, a 12-plate Oldershaw(vacuum-jacketed) distillation column and a distillazion head with thecapability of regulating the reflux ratio in a rough fashion, washing inwith additional methyl ethyl ketone (100 mL). Distill off 450 mL ofsolvent, cool to −15° C. and filter the solid. Wash with methyl ethylketone (2×100 mL) and dry to give the title compound (68.3 g, 99.9%); mp197–199° C.

Method E

Bring methyl ethyl ketone (4 mL) to a boil and add4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (500 mg). Decant the top layerand add methyl ethyl ketone (3 mL) to the aqeuous layer. Boil thesolution until the temperature reached 79° C., reduce the volume by 25%,remove from heat and cover with aluminum foil. Allow the solution tocool, filter the resulting crystals and air dry to give the titlecompound.

EXAMPLE 5 Conversion of Form I to Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate

Method A

Treat 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) (2.0 g) with ethanol(4 mL) and deionized water (20 mL). Heat at 80° C. until a solution isformed and then stir at room temperature for 23 hours. Filter theresulting slurry, wash with water (2×10 mL) and dry under vacuum at 35°C. overnight to give the title compound (1.88 g); mp 100–105° C.

XRPD: Table 6

TABLE 6 D-Space, Angstroms Intensity, I/I_(o), % 11.41 20 7.98 20 7.8345 6.58 45 6.42 60 5.66 20 5.52 45 5.39 30 5.23 65 5.14 45 4.86 65 4.72100 4.45 65 4.40 45 4.32 45 4.18 45 4.06 65 4.02 55 3.85 25 3.79 75 3.7495 3.61 80 3.56 25 3.47 65 3.41 20 2.74 20Method B

Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride (2.59 g).Add4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) (4.77 g). Heat to reflux on a steam bathuntil dissolution and cool to −10° C. Filter the resulting solid, washwith water (2×25 mL) and vacuum dry overnight to give the title compound(4.80 g).

EXAMPLE 6 Conversion of Form II into Form III4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

(Form III)

Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (55.56 g, 0.0929 mol having 10%water) in a pressure bottle along with water (2.96 g) and acetone (38.1g). Seal the bottle tightly and heat to approximately 80° C. Cool toabout 50° C., filter through filter aid in a coarse sintered glassfunnel and dilute with acetone (90 g). Transfer to a 1 L flask fittedwith a mechanical stirrer, thermometer and a reflux condenser. Heat themixture to reflux and allow to cool and stir over the weekend. Cool to−15° C. and filter on a coarse sintered glass funnel, wash with ethylacetate (2×50 mL) and vacuum dry at 50° C.

Place a majority of the solid obtained (45.24 g) in a 500 mL threenecked flask fitted with a mechanical stirrer, thermometer and a refluxcondenser. Add acetone (240 mL) and water (4.82 g) and reflux themixture overnight. Allow the slurry to cool to 35° C. and place in anice water bath and cool to less then 5° C. Filter the solid off on acoarse sintered glass funnel, wash with ethyl acetate (50 mL) and vacuumdry at 50 C. for several hours to give the title compound as a whitecrystalline powder (43.83 g, 97%); mp 166.5–170.5° C.

XRPD: Table 7

TABLE 7 D-Space, Angstroms Intensity, I/I_(o), % 8.95 95 4.99 20 4.88100 4.75 35 4.57 25 4.47 25 4.46 20 3.67 20 3.65 25

EXAMPLE 7 Conversion of Form III into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

(Form I)

Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) (40.0 g as an ethyl acetate wetcake-27.9 gdry basis) in a 1 L three necked flask fitted with a mechanical stirrer,thermometer and a reflux condenser. Add acetone (240 mL) and heat themixture to reflux for about 20 hours. Cool the slurry to −15° C. andisolate the solids by filtration on a coarse sintered glass frit funnel.Wash with ethyl acetate (50 mL) and vacuum dry overnight to give thetitle compound (26.1 g, 93.7%); mp 197.5–199.5° C.

XRPD: Table 8

TABLE 8 D-Space, Angstroms Intensity, I/I_(o), % 11.75 35 7.23 35 6.2460 5.89 40 5.02 20 4.94 30 4.83 100 4.44 30 3.93 75 3.83 20 3.77 85 3.7125 3.62 30 3.32 25 3.31 20

EXAMPLE 8 Conversion of Form IV into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

(Form I)

Place4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (54.35 g, 0.0970 mol, having 4%water present) in a pressure bottle along with water (4.16 g) andacetone (38.1 g). Seal the bottle tightly and heat to approximately 80°C. Cool to less then 60° C., filter through filter aid in a coarsesintered glass funnel and rinse the filter cake with acetone (32.4 g).Place acetone (215 g) in a 1 L three necked flask fitted with amechanical stirrer, thermometer, a reflux condenser and containing asmall amount of Form I crystals and heat to reflux. Add a portion of theacetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (47.65 g) to the refluxing acetoneover about 10 minutes. Slowly add ethyl acetate (157.5 g) over 45minutes then add the remaining portion of the acetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV), rinsed in with about 20 mL ofacetone. Add additional ethyl acetate (157.5 g) over 45 minutes to 1hour, maintaining the slurry at reflux. Stir for 15 minutes, cool to−15° C. and vacuum filter the white solid on a 350 mL coarse sinteredglass funnel. Wash the solids with ethyl acetate (2×50 mL) and vacuumdry overnight to give the title compound (50.36 g, 97%); mp 198–199.5°C.

XRPD: Table 9

TABLE 9 D-Space, Angstroms Intensity, I/I_(o), % 14.89 20 11.85 20 7.3020 6.28 70 5.91 25 5.55 20 5.05 25 4.96 55 4.85 100 4.57 45 4.45 55 3.9445 3.89 20 3.84 20 3.78 60 3.72 35 3.63 20 3.07 20 3.04 20 2.45 20

The polymorphic and pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention are useful asantihistamines, antiallergy agents and bronchodilators and may beadministered alone or with suitable pharmaceutical carriers, and can bein solid or liquid form such as, tablets, capsules, powders, solutions,suspensions or emulsions.

The polymorphic and pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention can be administeredorally, parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation or byapplication to mucous membranes, such as, that of the nose, throat andbronchial tubes, for example, in an aerosol spray containing smallparticles of a compound of this invention in a spray or dry powder form.

The quantity of polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound administered will vary depending on thepatient and the mode of administration and can be any effective amount.The quantity of polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound administered may vary over a wide range toprovide in a unit dosage an effective amount of from about 0.01 to 20mg/kg of body weight of the patient per day to achieve the desiredeffect. For example, the desired antihistamine, antiallergy andbronchodilator effects can be obtained by consumption of a unit dosageform such as a tablet containing 1 to 500 mg of a polymorphic orpseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound of this invention taken 1 to 4 times daily.

The solid unit dosage forms can be of the conventional type. Thus, thesolid form can be a capsule which can be the ordinary gelatin typecontaining a polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound of this invention and a carrier, forexample, lubricants and inert fillers such as lactose, sucrose orcornstarch. In another embodiment the polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compound is tableted with conventional tablet basessuch as lactose, sucrose or cornstarch or gelatin, disintegrating agentssuch as cornstarch, potato starch or alginic acid, and a lubricant suchas stearic acid or magnesium stearate.

The polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride compounds of this invention may also be administeredin injectable dosages by solution or suspension of the compounds in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils, with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils there can be mentioned those ofpetroleum, animal, vegatable or synthetic origin, for example, peanutoil, soybean oil or mineral oil. In general, water, saline, aqueousdextrose and related sugar solutions and glycols such as propyleneglycol or polyethylene glycol are preferred liquid carriers,particularly for injectable solutions.

For use as aerosols the compounds of this invention in solution orsuspension may be packaged in a pressurized aerosol container togetherwith suitable propellants, for example, hydrocarbon propellants such as,propane, butane or isobutane with the usual adjuvants as may beadministered in a non-pressurized form such as in a nebulizer oratomizer.

The term patient as used herein is taken to mean warm blooded animals,birds, mammals, for example, humans, cats, dogs, horses, sheep, bovinecows, pigs, lambs, rats, mice and guinea pigs.

1. Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride.